CN109553532B - Preparation method of 4-bromoacetyl-2-methyl benzoic acid methyl ester - Google Patents
Preparation method of 4-bromoacetyl-2-methyl benzoic acid methyl ester Download PDFInfo
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- CN109553532B CN109553532B CN201811570775.7A CN201811570775A CN109553532B CN 109553532 B CN109553532 B CN 109553532B CN 201811570775 A CN201811570775 A CN 201811570775A CN 109553532 B CN109553532 B CN 109553532B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention provides a preparation method of 4-bromoacetyl-2-methyl benzoic acid methyl ester, which comprises the following steps: a. dissolving 4-bromo-2-methylbenzoic acid in methanol, and carrying out an esterification reaction under the catalysis of sulfuric acid to generate a first intermediate compound; b. reacting the first intermediate compound with potassium vinylfluoroborate or vinylboric acid under the action of palladium catalysis to obtain a second intermediate compound; c. and carrying out alpha-halogenated ketone synthesis reaction on the second intermediate compound under the action of a halogenated reagent to obtain the 4-bromoacetyl-2-methyl benzoate. The preparation method has the advantages of low raw material cost, short route, mild reaction conditions, simple requirements on equipment and experimental conditions, realization of large-scale amplified synthesis and higher application value.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly relates to a preparation method of 4-bromoacetyl-2-methyl benzoate.
Background
Fluralaner, chemical name 4- [5- (3, 5-dichlorophenyl) -4, 5-dihydro-5-trifluoromethyl-3-isoxazolyl ] -2-methyl-nitrogen- [ 2-oxo-2- [ (2,2, 2-trifluoroethyl) amino ] ethyl ] -benzamide, of the formula:
fluralaner, a new ectoparasiticide, belongs to the isoxazolone class, and is a systemic drug for killing fleas and lice. The product can be used for controlling flea bite allergic dermatitis, and is marketed in Germany, Spain, Italy, France, the Netherlands and the United kingdom in 4 months 2014.
At present, the literature for synthesizing Fluralaner is less, and one feasible method is to use 4-bromoacetyl-2-methyl benzoate and 3, 5-dichlorotrifluoroacetyl benzene to close a ring, and then condense the ring with 2-amino-N- (2,2, 2-trifluoroethyl) acetamide to generate a Fluralaner target compound.
Wherein the structure of the 4-bromoacetyl-2-methyl benzoic acid methyl ester is as follows:
at present, no relevant documents are reported, so that the preparation of the methyl 4-bromoacetyl-2-methylbenzoate is important.
Disclosure of Invention
The invention mainly aims to develop a preparation method of methyl 4-bromoacetyl-2-methylbenzoate.
The technical route of the invention is to obtain the target product 4-bromoacetyl-2-methyl benzoate by using 4-bromo-2-methyl benzoic acid as an initial raw material and carrying out three-step reactions of esterification, palladium catalytic reaction and haloketone synthesis. The invention aims to synthesize 4-bromoacetyl-2-methyl benzoate, which comprises the following steps:
a. dissolving 4-bromo-2-methylbenzoic acid in methanol, and carrying out an esterification reaction under the catalysis of sulfuric acid to generate a first intermediate compound;
b. reacting the first intermediate compound with potassium vinylfluoroborate or vinylboric acid under the action of palladium catalysis to obtain a second intermediate compound;
c. and carrying out alpha-halogenated ketone synthesis reaction on the second intermediate compound under the action of a halogenated reagent to obtain the 4-bromoacetyl-2-methyl benzoate.
The reaction equation is:
in the step b, palladium catalysis is performed by using palladium tetratriphenylphosphine, palladium acetate and Pd (dppf) Cl2 、Pd(PPh3)2Cl2Any one of them is used as a catalyst.
In step b, Pd (dppf) Cl is used for palladium catalysis2Is a catalyst, and the molar weight of the catalyst is 3 to 5 percent of the reaction raw material.
And c, using a mixed solvent as a solvent for the reaction in the step b, wherein the mixed solvent is a mixed solvent of any one of dioxane, N-dimethylformamide, ethylene glycol dimethyl ether and acetonitrile and water.
The solvent used in the reaction in the step b is a mixed solvent of N, N-dimethylformamide and water, the mass ratio is 4:1, and the dosage of the solvent is 8-10 times of that of a reaction substrate.
The alkali used in the reaction in the step b is any one or more of potassium carbonate, sodium carbonate, potassium phosphate and cesium carbonate.
The alkali used in the reaction in the step b is sodium carbonate, and the molar ratio of the sodium carbonate to the reaction raw materials is 3:1-4: 1.
In the step c, a halogenated reagent is any one of bromosuccinimide, chlorosuccinimide and dibromohydantoin, and a solvent used in the step c is a mixed solvent of water and any one of tetrahydrofuran, acetonitrile and dioxane.
In the step c, a halogenated reagent is bromosuccinimide, the molar ratio of the bromosuccinimide to the reaction raw materials is 1.2:1-1.5:1, the solvent used in the step c is a mixed solvent of tetrahydrofuran and water, the mass ratio is 1:1-2:1, and the dosage is 6-10 times of that of the substrate.
The technical route of the invention is to obtain the target product 4-bromoacetyl-2-methyl benzoate by using 4-bromo-2-methyl benzoic acid as an initial raw material and carrying out three-step reactions of esterification, palladium catalytic reaction and haloketone synthesis. The method provides a new technical scheme for the source of the synthetic raw material of Fluralaner. The preparation method has the advantages of low raw material cost, short route, mild reaction conditions, simple requirements on equipment and experimental conditions, realization of large-scale amplified synthesis and higher application value.
Detailed Description
Hereinafter, preferred examples of the invention will be described in detail. The examples are given for the purpose of better understanding the inventive content and are not intended to be limiting. Insubstantial modifications and adaptations of the embodiments in accordance with the present disclosure remain within the scope of the invention.
Synthesis of first intermediate Compound
In a 500ml single-neck flask, 4-bromo-2-methylbenzoic acid (20 g, 9.3 mmol) was added, methanol 160g was added, concentrated sulfuric acid 2ml was added, heating and refluxing were performed for 6 hours, TLC detection reaction was completed, ethyl acetate hydrate was added, extraction was performed 2 times, anhydrous sodium sulfate was dried, and drying was performed to obtain a white solid first intermediate compound (methyl 4-bromo-2-methylbenzoate).
Synthesis of second intermediate Compound
In a 500ml single-neck flask, methyl 4-bromo-2-methylbenzoate (first intermediate compound) (15 g, 6.6 mmol) was charged, tetrahydrofuran 90g, water 22.5 g were added, solid sodium carbonate (2.1 g, 19.8 mmol) was added, Pd (dppf) Cl was added2(241 mg, 0.33 mmol), nitrogen was replaced three times, the reaction was heated to 110 ℃ for 4 hours, TLC monitored the completion of the reaction, cooled, water and ethyl acetate were added, filtered, separated, extracted twice, backwashed with saturated saline, washed once with water, dried with anhydrous sodium sulfate, and the solvent was evaporated to dryness to give a second intermediate compound (10.7g) as a pale yellow oil in 92% yield.
1HNMR （400Hz，CDCl3）δ:7.88-7.90（d，1H）, 7.29-7.27（d，1H）,7.26(s，1H),6.66-6.73(q，1H),5.81-5.86(d，1H),5.32-5.36 (d，1H),3.88(s，3H),2.60（s，3H）。
Synthesis of methyl 4-bromoacetyl-2-methylbenzoate
In a 100ml single-neck flask, the second intermediate compound (12g,68.2mmol) is added, solvent tetrahydrofuran 60g is added, water 60g is added, bromosuccinimide (14.4 g, 81.8 mmol) is added, the mixture is heated to 80 ℃ to react for 8 hours, after the completion of the reaction is monitored, water and ethyl acetate are added to the reaction liquid, liquid separation and extraction are carried out twice, the organic phases are combined, the mixture is washed with saturated saline, anhydrous magnesium sulfate is dried, solvent is filtered and evaporated, and the crude product is crystallized to obtain the target product (13.6 g) with the yield of 74 percent.
1HNMR （400Hz，CDCl3）δ:7.97-7.99（d，1H）, 7.81-7.84（m，2H）,4.46(s，2H), 3.92(s，3H),2.65（s，3H）。
Claims (5)
1. A preparation method of 4-bromoacetyl-2-methyl benzoic acid methyl ester is characterized by comprising the following steps:
a. dissolving 4-bromo-2-methylbenzoic acid in methanol, and carrying out esterification reaction under the catalysis of sulfuric acid to generate a first intermediate compound, namely 4-bromo-2-methylbenzoic acid methyl ester;
b. reacting the first intermediate compound with potassium vinylfluoroborate or vinylboric acid under the action of palladium catalysis to obtain a second intermediate compound;
c. the second intermediate compound is subjected to alpha-halogenated ketone synthesis reaction under the action of a halogenated reagent to obtain 4-bromoacetyl-2-methyl benzoate;
in the step b, palladium catalysis is performed by using palladium tetratriphenylphosphine, palladium acetate and Pd (dppf) Cl2 、Pd(PPh3)2Cl2Any one of them is used as a catalyst;
the solvent used in the reaction in the step b is a mixed solvent, and the mixed solvent is a mixed solvent of any one of dioxane, N-dimethylformamide, ethylene glycol dimethyl ether and acetonitrile and water;
the alkali used in the reaction in the step b is any one or more of potassium carbonate, sodium carbonate, potassium phosphate and cesium carbonate;
in the step c, a halogenated reagent is any one of bromosuccinimide, chlorosuccinimide and dibromohydantoin, and a solvent used in the step c is a mixed solvent of water and any one of tetrahydrofuran, acetonitrile and dioxane.
2. The method according to claim 1, wherein in step b, Pd (dppf) Cl is used as a catalyst in the form of Pd (dppf)2Is a catalyst, and the molar weight of the catalyst is 3 to 5 percent of the reaction raw material.
3. The process according to claim 1, wherein the solvent used in the reaction in step b is a mixed solvent of N, N-dimethylformamide and water, the mass ratio of the mixed solvent to the mixed solvent is 4:1, and the amount of the solvent is 8 to 10 times the mass of the reaction substrate.
4. The process according to claim 1, wherein the base used in the reaction in step b is sodium carbonate, and the molar ratio of the sodium carbonate to the reaction raw material is 3:1 to 4: 1.
5. The preparation method of methyl 4-bromoacetyl-2-methylbenzoate according to claim 1, wherein the halogenating agent used in the step c is bromosuccinimide, the molar ratio of the bromosuccinimide to the reaction raw material is 1.2:1-1.5:1, and the solvent used in the step c is a mixed solvent of tetrahydrofuran and water, the mass ratio is 1:1-2:1, and the amount of the solvent is 6-10 times of the mass of the substrate.
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| CN110015960A (en) * | 2019-05-08 | 2019-07-16 | 大连大学 | The preparation method and application of 1,3- bis- (4,4- methyl formate phenyl) acetone |
| CN115477577B (en) * | 2022-10-25 | 2024-03-15 | 台州臻挚生物科技有限公司 | New method for preparing 2-methyl-4-acetyl benzoic acid and derivatives thereof |
Citations (3)
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| WO2010118208A1 (en) * | 2009-04-09 | 2010-10-14 | Exelixis, Inc. | Benzoxazepin-4- (5h) -yl derivatives and their use to treat cancer |
| WO2013018735A1 (en) * | 2011-07-29 | 2013-02-07 | 大正製薬株式会社 | Amidine compound or salt thereof |
| CN108069839A (en) * | 2016-11-10 | 2018-05-25 | 复旦大学 | Alkene is converted into the method for alpha- bromo ketone using C5H6Br2N2O2 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010118208A1 (en) * | 2009-04-09 | 2010-10-14 | Exelixis, Inc. | Benzoxazepin-4- (5h) -yl derivatives and their use to treat cancer |
| WO2013018735A1 (en) * | 2011-07-29 | 2013-02-07 | 大正製薬株式会社 | Amidine compound or salt thereof |
| CN108069839A (en) * | 2016-11-10 | 2018-05-25 | 复旦大学 | Alkene is converted into the method for alpha- bromo ketone using C5H6Br2N2O2 |
Non-Patent Citations (3)
| Title |
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| 2-甲基-4-甲醛肟基苯甲酸甲酯的合成;黄道友等;《化学试剂》;20170731;第39卷(第7期);第776-778页 * |
| Facile one-pot synthesis of alpha-bromoketones from olefins using bromide/bromate couple as a nonhazardous brominating agent;Patil, Rajendra D et al;《TETRAHEDRON LETTERS》;20090313;第50卷(第21期);第2529-2532页 * |
| Synthesis of phenacyl bromides via K2S2O8-mediated tandem hydroxybromination and oxidation of styrenes in water;Jiang, Qing et al;《GREEN CHEMISTRY》;20131231;第15卷(第8期);第2175-2179页 * |
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